tbuckley/cabot-search huggingface dataset:
Decision making support for cancer patient's treatment strategy during the COVID-19 pandemic in Japan.
Authors: Shiori Yoshida, Fumiko Sato, Konosuke Sasaki, Rie Sasaki
Journal: Journal of Clinical Oncology (2022)

e24141 Background: During the COVID-19 pandemic, cancer patients became reluctant to come to the hospital, receive cancer treatment, and were willing to interrupt or postpone treatment due to concerns about infection. The purpose of this study was to discuss effective treatment strategy decision making support for cancer patients during the COVID-19 pandemic. Methods: An online survey was conducted on decision making support among nurses who worked at a cancer care hospital in Japan from May to July 2021. Results: Forty-nine facilities were asked to participate in the survey, and replies were received from 728 respondents; 185 (26.8%) were nurses engaged in the decision making. The most common treatment choice was postponement in 132 patients (73.3%). Nurses who “provided information on measures to prevent COVID-19 infection” were more likely to recognize that “the patient was satisfied with the treatment” (p &lt; 0.05). Nurses who “listened to the patient's thoughts” were less likely to perceive that the patient was “not convinced and continued with the previous treatment” (p &lt; 0.05). Nurses who “listened to the patient's intentions and thoughts after the decision was made,” “followed up on the patient's symptoms and changes in perceptions by telephone,” “followed up on the patient's symptoms and changes in perceptions by videophone”, and “assured the patient that they could take immediate action if symptoms worsened with the physician's permission” more often recognized that the patient “accepted the treatment recommended by the physician although they were not convinced” (p &lt; 0.05). Conclusions: Effective treatment strategy decision making support for cancer patients during the COVID-19 pandemic includes lifestyle guidance for infection prevention, listening to identify the reasons behind patients’ choices, and telenursing for follow-up decision.
The effect of PARP inhibition on androgen receptor localization and activity in castration resistant prostate cancer.
Authors: Emily Nizialek, Michael Haffner, Akshay Bhamidipati, Srinivasan Yegnasubramanian
Journal: Journal of Clinical Oncology (2022)

e17037 Background: The poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib and rucaparib have been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in the setting of homologous recombination deficiency (HRD). Additionally, PARPi have been shown to modulate androgen receptor (AR) signaling, with a recent report demonstrating mono-ADP-ribosylation of cysteine residues in AR by Parp7. Here, we further evaluated the effect of PARPi on AR activity and localization. Methods: The effect of PARPi on cell growth and survival of CRPC cell lines was evaluated in vitro and in vivo. AR ribosylation was assessed in CRPC cell lines by immunoprecipitation (IP) assays and proximity ligation assays (PLA). The subcellular localization of AR was determined by quantitative immunofluorescence microscopy in CRPC cell lines and xenograft models. Changes in AR activity with PARPi treatment were evaluated by a luciferase reporter assay and AR target gene expression in a PDX model. Finally, PARPi mediated alteration in the AR protein interactome was evaluated by liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomics. Results: The PARPi olaparib and talazoparib, and to a lesser extent veliparib, inhibited CRPC cell growth. Evidence of AR ribosylation was seen by IP and PLA. PARPi treatment of multiple in vitro and in vivo prostate cancer models resulted in a shift of AR subcellular localization, from predominantly nuclear to cytoplasmic compartments. In luciferase reporter assays, AR transactivation activity was decreased after PARPi treatment in a dose dependent manner. In vivo, in prostate cancer xenograft models, decreased AR target gene expression was seen upon PARPi treatment. LC-MS/MS proteomic studies revealed that PARP inhibition resulted in significant changes in the composition of AR interaction partners, in particular of proteins related to intracellular trafficking and nuclear transport. This suggests a potential link between altered AR complex assembly and the observed changes in AR subcellular localization in the context of PARPi treatment. Conclusions: We describe a novel sequela of PARPi therapy to alter AR localization and activity in CRPC. Single agent PARP inhibition can alter prostate cancer cell growth in vitro and in vivo. With PARPi treatment, AR localization is shifted to the cytoplasm, the AR interactome is altered, and AR transcriptional activity decreased. These findings implicate a collateral mechanism of PARPi in preventing prostate cancer cell growth/survival that may augment previously described mechanisms related to HDR and synthetic lethality. It is essential to understand the role of PARPi beyond synthetic lethality in the context of HRD in order to better define the spectrum of response to PARPi across patients, and for development of biology-informed combination therapies.
Analysis of miRNA profile in circulating extracellular vesicles of patients with pulmonary arterial hypertension
Authors: A Khandagale, P Corcoran, M Nikpour, A Siegbahn, C Christersson
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Swedish Research Council Introduction Pulmonary arterial hypertension (PAH) is characterized by a progressive elevation of pulmonary pressure leading to right ventricular dysfunction and is associated with a poor prognosis. Patients with PAH have increased numbers of circulating extracellular vesicles (EVs), which are small membrane vesicles (&amp;lt;1 µm) released from different cells. EVs contain surface antigens, proteins and genetic material, and serve as vectors of intercellular communication. MicroRNAs (miRs) are small RNAs that act as post-transcriptional regulators inhibiting gene expression. Alteration of miR expression is associated with stage, progression and severity of different diseases making them suitable as potential biomarker. The aim of the study was to evaluate the miRNA profile contained in EVs derived from plasma of both control healthy subjects and patients with PAH. Methods Circulating EVs, purified from platelet free plasma, from 9 healthy controls (HC) and 10 PAH patients were analyzed. After total RNA isolation, fixed volumes of total RNA were biotinylated to generate fragmented cRNA. Samples were then subjected to Microarray analysis using GeneChip miRNA 4.0 Array. Data was further analysed using various bioinformatics tools. Results Total of 762 miRs were identified while comparing PAH vs HC groups, of which 22 were found to be down-regulated and 3 were up-regulated in PAH group (Table 1). Gene ontology enrichment analysis revealed various cell signaling pathways where-in identified miRs are involved. Conclusions PAH patients pack and transport a differentiated expression profile of miRs, suggesting that EVs might serve as signaling vectors. Further analyses of the functionality of EVs' miRs is currently undergoing in our lab to understand its role during PAH progression and/or inhibition.
Transcriptomic perspectives of memory-like NK cells and aging
Authors: Dandan Wang, Subramaniam Malarkannan
Journal: Genome Medicine (2022)

A recent study highlights the presence of a unique memory-like natural killer (NK) cell subset, which accumulates with aging and appears to associate withdisease severity in COVID-19 patients. While the clinical relevance of memory in NK cells is being debated, the molecular identity of this subset in the form of a single-cell transcriptome is essential to define their origin, longevity, functions, and disease relevance.
Recurrent Plant-Specific Duplications of KNL2 and its Conserved Function as a Kinetochore Assembly Factor
Authors: Sheng Zuo, Ramakrishna Yadala, Fen Yang, Paul Talbert, Joerg Fuchs, Veit Schubert, Ulkar Ahmadli, Twan Rutten, Ales Pecinka, Martin A Lysak, Inna Lermontova
Journal: Molecular Biology and Evolution (2022)

KINETOCHORE NULL2 (KNL2) plays key role in the recognition of centromeres and new CENH3 deposition. To gain insight into the origin and diversification of the KNL2 gene, we reconstructed its evolutionary history in the plant kingdom. Our results indicate that the KNL2 gene in plants underwent three independent ancient duplications in ferns, grasses and eudicots. Additionally, we demonstrated that previously unclassified KNL2 genes could be divided into two clades αKNL2 and βKNL2 in eudicots and γKNL2 and δKNL2 in grasses, respectively. KNL2s of all clades encode the conserved SANTA domain, but only the αKNL2 and γKNL2 groups additionally encode the CENPC-k motif. In the more numerous eudicot sequences, signatures of positive selection were found in both αKNL2 and βKNL2 clades, suggesting recent or ongoing adaptation. The confirmed centromeric localization of βKNL2 and mutant analysis suggests that it participates in loading of new CENH3, similarly to αKNL2. A high rate of seed abortion was found in heterozygous βKNL2 plants and the germinated homozygous mutants did not develop beyond the seedling stage. Taken together, our study provides a new understanding of the evolutionary diversification of the plant kinetochore assembly gene KNL2, and suggests that the plant-specific duplicated KNL2 genes are involved in centromere and/or kinetochore assembly for preserving genome stability.
Impact of perioperative chemotherapy on survival outcome of advanced colorectal cancer patients treated with cytoreduction and hyperthermic intraperitoneal chemotherapy: A retrospective study.
Authors: Shereef Ahmed Elsamany, Saleh Alzahrani, Abdulaziz Alzahrani, Ammar Bukhari, Amr Arbaein, Fayza Hassanin, Hani Elkhatib
Journal: Journal of Clinical Oncology (2022)

e15570 Background: Colorectal cancer (CRC) with peritoneal carcinomatosis (PC) is generally associated with poor prognosis. The present study aims to assess potential value of perioperative systemic chemotherapy in patients treated with cytoreductive surgery with HIPEC (CRS/HIPEC) in a single institute in Saudi Arabia. Methods: We included CRC with PC who underwent CRS/ HIPEC from January 2012 till December 2019. Different clinicopathological, treatment-related factors and dates of relapse/death, were retrospectively assessed. We checked the distribution of these factors in addition to survival outcome in those who received perioperative chemotherapy vs. none. Results: We recruited 127 eligible patients (79 patients [62.2%] received systemic chemotherapy). Patients with no perioperative chemotherapy were more likely to have grade 1 tumours (62.5% vs. 25.3%, p &lt; 0.0001), mucinous adenocarcinoma (41.7% vs. 12.7%, p = 0.002), normal CEA ≤5 ng/dl (70.2% vs. 47.4%, p = 0.016) and peritoneal-only metastasis (66.7% vs. 45.6%, p = 0.021). Median PFS and OS were 34 and 62.2 months, respectively. Patients with no perioperative systemic chemotherapy had significantly better PFS and OS (median PFS: not reached vs. 19 months, HR = 0.29, 95% CI = 0.15-0.59, p &lt; 0.0001, OS :HR = 4.3, 95% CI 1.3-14.3, p = 0.009). After adjustment of different prognostic factors, there was no significance difference in OS between the two groups (HR = 3.8, 95% CI = 0.98-14.71, p = 0.053), while PFS was still significantly better in the no chemotherapy group (HR = 2.52, 95% CI = 1.13-5.63, p = 0.024). Conclusions: CRS/HIPEC provided favourable survival outcome in our study cohort especially in patients with more favourable prognostic features. No survival benefit with perioperative chemotherapy could be demonstrated.
Consensus on the utility of breast cancer multigene signatures in routine clinical practice: Results of the PROCURE Project.
Authors: Giuseppe Curigliano, Fatima Cardoso, Michael Gnant, Nadia Harbeck, Judy W. King, Anne-Vibeke Laenkholm, Frederique Penault Llorca, Aleix Prat
Journal: Journal of Clinical Oncology (2022)

e13639 Background: Several Breast Cancer Multigene Signatures (BCMS) are available to profile early breast cancer (eBC) that according to current evidence, can provide reliable information on the risk of recurrence but the knowledge regarding their real use in clinical practice is scarce. The PROCURE Project aims to establish recommendations on the use of BCMS in clinical practice. Methods: A Scientific Committee consisting of 8 European experts in BC, including oncologists, pathologists, and surgeons, developed a Delphi questionnaire that was administered twice to clinicians across different European centers. The questionnaire included 5 sections: 1) Panelists’ profile and experience with BCMS, 2) Current clinical practice in eBC and use of BCMS, 3) Panelists’ opinion on the utility of the BCMS in eBC according to patient profiles, 4) Agreement with a set of recommendations on the use of BCMS in clinical practice and 5) Identification of unmet needs and future applications of BCMS. 70% agreement was used to determine consensus on a topic. Results: 133 panelists from 11 European countries completed both rounds of the survey. Most of the panelists worked in a teaching hospital (86.5%) and 72.2% of them were medical oncologists. 93.6% of the panelists used BCMS routinely or in selected patients and 73.4% had more than 5 years of experience using BCMS. According to panelists, for being useful in clinical practice BCMS should consider clinical and pathological features of the disease (91%). Additionally, BCMS must provide both, prognostic and predictive information (82%), and information on the risk of late distant recurrence from 5 to 10 years (74%), all based on prospective randomized clinical trials (85%). BCMS must also provide accurate results to guide adjuvant chemotherapy decision (81%). Regarding recommendations for improving BCMS utility, 76% of the panelists agreed that hospitals policies on the use of BCMS must be based on clinical practice guidelines. Panelists also agreed that patients should have the right to access their BCMS results to take part in the treatment decision (86%) and more training is needed for patients (79%) as well as oncologists (84%) and pathologists (82%). Finally, panelists mostly disagree on the fact that BCMS must be performed in all patients when BC is suspected (76%). Conclusions: The high degree of importance that panelists attributed to the fact that a BCMS should provide both prognostic and predictive information, reflects a misconception on the utility of BCMS as they are primarily prognostic tools but not predictive about the effect of a therapeutic intervention. Also, consensus reached on the need of providing risk of late recurrence from 5 to 10 years shows that panelists evaluate the long-term treatment even in the early setting.
Cardiotoxicity in patients on anthracyclines and traztuzumab: Identifying risk factors and echocardiographic parameters.
Authors: Kanak Parmar, Andrew Jones, Duke Appiah, Catherine Jones, Miguel Quirch, Dushyant Pawar, Gaspar Del Rio Pertuz, Tung Nguyen, Cristina Morataya, Pooja Sethi
Journal: Journal of Clinical Oncology (2022)

e24052 Background: Anthracyclines and human epidermal growth factor receptor 2(HER-2) directed therapy are widely used as chemotherapy in various cancers. Up to 10% of patients treated with anthracyclines will develop reduction in left ventricle ejection fraction (LVEF), and cardiotoxicity by HER-2 directed therapy can be as high as 35%. The drop in EF is often late and changes may not be reversed at that point. Strain imaging using global longitudinal strain (GLS) has potential for detecting cardiotoxicity earlier however guidelines remain to be standardized. The objective of this study is to study variations in GLS over time as well as evaluate the relation of patient characteristics with various echocardiographic parameters. Methods: Linear mixed effects models with random intercepts were used to evaluate trends in EF and GLS over time and model the association of cancer therapy and patient characteristics with repeated measures of GLS and EF. Patients were enrolled in the study from 2018-2021 who received anthracycline, or HER-2 targeted treatment for any cancer and had serial echocardiography. Results: In the overall cohort there were more females (61%) than males (20%) in the study. Most patients had breast cancer (67%), followed by leukemia (14%) and lymphoma (13%).35% patients were in the younger age group (&lt; 65 years) and 46% patients were in the older age (≥65 years). There was a significant change in GLS in older patients at 7-9 months (-15 SE 0.6) and 10-12 months (-14 SE 1) (P 0.006; P 0.001). Only 13 patients out of 81 patients developed cardiotoxicity as defined by the current consensus guidelines based on LVEF. Further analysis was then performed between these two groups at various time intervals. LV end diastolic volume (LVEDV) at baseline was significantly higher in the cardiotoxic group (P 0.016). GLS at baseline in both groups had no statistical difference. However, GLS began to show significant differences in the initial 1-3 months in the cardiotoxic group (-14; SE 0.9) as compared to the non-cardiotoxic group (-17.03; SE 0.3) (P 0.003). This difference persisted over various time points from 4 months till 1 year (P &lt; 0.0001 at all points). Conclusions: Our data suggests that GLS may be used as a measure to identify patients who will develop cardiotoxicity by obtaining it at baseline and early during treatment. Higher baseline LVEDV was associated with development of cardiotoxicity. Older patients tend to have more drop in GLS and frequent measures will help to detect cardiotoxicity in this group.
Increasing primary care utilization prior to cancer diagnosis in association with cancer mortality.
Authors: Edmund Men Qiao, Kripa Guram, Nikhil V. Kotha, Rohith S. Voora, Alexander Qian, Grace S. Ahn, Sandhya Kalavacherla, Ramona Pindus, Tyler F. Stewart, Matthew P. Banegas, James Don Murphy, Brent S. Rose
Journal: Journal of Clinical Oncology (2022)

10548 Background: Primary care physicians (PCPs) are significant contributors of early cancer detection yet few studies have investigated whether consistent primary care translates to improved downstream outcomes. We evaluated the impact of prior PCP utilization on metastatic disease at diagnosis and cancer-specific mortality (CSM) for a general cancer cohort and 12 tumor subtypes. Methods: We identified cancer patients ≥40 years, diagnosed from 2004-2017 within the Veterans Health Administration. For our 5-year pre-diagnostic period, we binned PCP visits into none (0 visits), some (1-4), and annual (5). Multivariable logistic regression assessed the effect of PCP utilization on metastatic disease at diagnosis and Fine-Gray regression with non-cancer death as a competing event evaluated their effect on cancer-specific mortality (CSM). These were repeated for each subtype. Results: Among 245,425 patients, mean age was 66 years with 5.7-year median follow-up. Compared with 0 visits, some PCP utilization was associated with 26% reduced odds of metastatic disease at diagnosis (odds ratio (OR), 95% confidence interval (CI): 0.74 [0.71-0.76] P&lt;0.01) and 12% lower risk of CSM (hazard ratio (HR), 95% CI: 0.88 [0.86-0.89] P&lt;0.01). Annual PCP utilization was associated with 39% reduced odds of metastatic disease (OR, 95% CI: 0.61 [0.59-0.63] P&lt;0.01) and 21% lower risk of CSM (HR, 95% CI: 0.79 [0.77-0.81] P&lt;0.01). Among subtypes, prostate cancer had the largest effect size for PCP utilization on metastatic disease at diagnosis (OR annual , 95% CI: 0.32 [0.30-0.35] P&lt;0.01) and CSM (HR annual , 95% CI: 0.51 [0.48-0.55] P&lt;0.01). Pancreas cancer had the lowest effect size on metastatic disease at diagnosis (OR annual , 95% CI: 0.87 [0.73-1.04] P: 0.12) and CSM (HR annual , 95% CI: 0.89 [0.82-0.97] P&lt;0.01). The table displays additional subtypes. Conclusions: Increased PCP utilization prior to cancer diagnosis is associated with a significant decrease in metastatic disease at diagnosis and CSM, with annual utilization associated with the greatest decrease. These results are consistent when stratifying by tumor subtype. Consistent primary care must be emphasized for patients at risk of cancer. [Table: see text]
Factors associated with U.S. hospital payer-specific negotiated mammography charges.
Authors: Kristin Hsieh, Hsin-Hui Huang, Elizabeth Stieglitz Tarras, Ellerie Weber, Deborah Catherine Marshall
Journal: Journal of Clinical Oncology (2022)

e13633 Background: The Hospital Price Transparency Rule, effective 1/1/2021, requires hospitals to publish payer-specific negotiated charges and cash prices. Given differences in insurance coverage for screening versus diagnostic mammography, we evaluate factors associated with these payer-negotiated charges. Methods: We conducted a cross-sectional study of U.S. acute care and critical access hospitals in CMS’ Care Compare linked to Turquoise Health (payer-negotiated charges), Healthcare Cost Report Information System (hospital characteristics) and Social Vulnerability Indices by county. Negotiated charges for mammography (CPT: screening 77067; diagnostic unilateral 77065, bilateral 77066) were estimated by payer type (self-pay, managed Medicare/Medicaid, or commercial). Adjusted models estimated commercial charges accounting for hospital factors. Results: Most hospitals (N=4212) were non-profits (61%) and acute care hospitals (69%). Median operating margin was .03 (IQR:-.03, .09), asset-to-liability ratio was 1.79 (1.06, 2.96), and social vulnerability index was .53 (.29, .74). 48-50% reported mammography charges. Charges were greater for commercial insurance compared to Medicare/Medicaid (+$55-$82 screening, +$122-$132 bilateral diagnostic; P&lt;.001, all tests). Charges for commercial insurance were similar to self-pay for bilateral screening (p=.41) and diagnostic (p=.08) mammography. See Table for adjusted analysis of commercial charges. Conclusions: Our analysis showed U.S. negotiated mammography charges are similar for self-pay and commercial payers. Commercial charges are higher at private hospitals and those with higher operating margins for diagnostic exams, and lower in socially vulnerable areas. Price transparency may promote competition to lower healthcare prices and highlight any financial toxicity associated with self-pay charges. [Table: see text]